Phenylalanine dipeptide derivatives, compositions and use thereof

Abstract

Disclosed are a compound of formula I, stereoisomers, pharmaceutically acceptable salts or hydrates thereof, a pharmaceutical composition comprising the same, a process for preparing the same and use thereof. The compound may also be used to prepare a medicament to treat viral infections, especially to prepare a medicament to treat hepatitis B virus and human immunodeficiency virus with little toxic side effects.

What is claimed is: 
     
       1. A compound of formula I and pharmaceutically acceptable salts thereof, 
       
         
           
           
               
               
           
         
       
       wherein,
 each R 1 , R 2  and R 3  independently represent a single substituent, wherein R 1  is independently selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, OH, OCOR, OR and O(CH 2 ) n NRR′; 
 R 3  is selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, and CH 2 NRR′; 
 R 2  is selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, NHOC(CH 2 ) n NRR′; OH, OCOR, OR, O(CH 2 ) n NRR′, O(CH 2 ) n COOH, CN, CH 2 NRR′, COOH, C 1 -C 6  alkyl, halo, (1-pyrrolidyl) acetamido, 
 
       
         
           
           
               
               
           
         
         R 4  is selected from the group consisting of CH 2 OH, COOR, CH 2 OCOC 2 -C 6  (linear or branched alkyl), CH 2 OCOC 3 -C 7  cycloalkyl, CH 2 OCO(CH 2 ) n COOH, COONa and —COOH; 
         each R and R′ in the R 1  to R 4  described above represent identical or different, linear or branched C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl; 
         said alkyl and cycloalkyl may be further optionally substituted with one or two substituents selected from the group consisting of OH, NO 2 , CN, CF 3  and halo; 
         X is CH or N; and 
         n is an integral number of 1 to 4; 
         with the proviso that the following compounds are excluded where: 
         X is CH, R 1  is CH 2 N(CH 3 ) 2 , R 2  is H, R 3  is H, and R 4  is CH 2 OH or CH 2 OCOMe; 
         X is CH, R 1  is H, R 2  is NHCH 2 CH 2 N(CH 3 ) 2 , R 3  is H, and R 4  is CH 2 OH or CH 2 OCOMe; 
         X is CH, R 1  is H, R 2  is H, R 3  is CH 2 N(CH 3 ) 2 , and R 4  is CH 2 OH or CH 2 OCOMe; 
         X is CH, each R 1 , R 2  and R 3  are H, and R 4  is CH 2 OH. 
       
     
     
       2. The compound of  claim 1 , wherein R 2  is selected from the group consisting of H, NO 2 , NHCOR, NHCO(CH 2 ) n COOH, OH, OCOR, O(CH 2 ) n NRR′, CH 2 NRR′, C 1 -C 6  alkyl, halo, (1-pyrrolidyl) acetamido, 
       
         
           
           
               
               
           
         
       
       and COOH. 
     
     
       3. The compound of  claim 1 , wherein R 1  is selected from the group consisting of H, NO 2 , NHCOCH 3 , NHCOCH2CH3, N(CH 3 ) 2 , NHCO(CH 2 ) 2 COOH, OH, OCH 3 , OCOCH 3 , O(CH 2 ) 2 N(CH 3 ) 2  and OCH 2 COOH. 
     
     
       4. The compound of  claim 1 , wherein R 3  is selected from the group consisting of H, NO 2 , NHCOCH 3 , and NHCOCH 2 CH 3 . 
     
     
       5. The compound of  claim 1 , wherein R 2  is selected from the group consisting of H, F, C1, NO 2 , NHCOCH 3 , NHCOCH 2 C1, NHCOCH 2 CH 3 , NHCO(CH 2 ) 2 COOH, NHCOCH 2 N(CH 3 ) 2 , OH, OCOCH 2 CH 3 , O(CH 2 ) 2 N(CH 3 ) 2 , CH 3 , CH 2 N(CH 3 ) 2 , COOH, (1-pyrrolidyl)acetamido, 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , wherein R 4  is selected from the group consisting of CH 2 OH, COOCH 3 , CH 2 OCOCH 3 , CH 2 OCOCH 2 CH 3 , CH 2 OCOCH 2 COOH, CH 2 OCO(CH 2 ) 2 COOH, COONa and COOH. 
     
     
       7. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.